EE: Hello, I’m Eleni Efstathiou and we’re here in very good company in San Francisco quite early in the year, so Happy New Year. 7th January GU ASCO, never happened before has it? I don’t think so. But anyway we’re enjoying good weather which was not anticipated but also a great first day of ASCO discussing prostate cancer, what else? With me Axel Merseburger from Germany, a urologist, Nick James, becoming extremely famous this year, clinical oncologist which means that he practices both medical oncology and radiation oncology, and of course the famous Karim Fizazi from France. So gentlemen, you’re going to enlighten us today of what’s going on in prostate cancer for 2016. Axel, I think you should pick the most difficult part which is local disease, not a lot was said today. What was your take home message for your practice moving forward?
AM: Well Eleni, thank you for your introduction and thank you for having us here. My experience from the first day, it was very exciting, a lot of data and my take home message from local therapy was the presentation by Professor Shipley focussing on the topic of salvage therapy. There we have the discussion on when to start since years but now a novel aspect came into play – the use of ADT. I thought it was very interesting, he presented a trial on 24 months 150mg bicalutamide in combination with salvage therapy, radiation therapy, compared to just the standard…
NJ: Yes, just radiotherapy alone.
AM: Just radiotherapy alone. What is ground breaking for clinical practice was the news that you had an overall survival benefit from 78 to 82 months, also a reduction of prostate cancer death rate in this situation and also a reduction of occurrence of metastatic disease. So I thought this is something I would take home from San Francisco to Germany to communicate to my colleagues and I would like to hear your opinion, from an interdisciplinary view, if we should use this as standard of therapy. I think it might be advised from looking at the side effects.
EE: Are you going to?
AM: I will, yes.
EE: You will, as of tomorrow?
AM: Yes, as of tomorrow.
EE: Nick?
NJ: Yes, it’s been a very hot topic in the UK because in most settings where we use radiotherapy we use hormone therapy as well and androgen deprivation therapy as opposed to anti-androgen therapy which, of course, is what bicalutamide is. When UK practice was surveyed, and Chris Parker is the guy that has done a lot of the running on this in the UK, there was a big range that some people did, some people did not give hormone therapy. So there’s a big trial recruited out in the UK now called RADICALS which is randomising no hormone therapy, 6 months androgen deprivation and 24 months. That’s finished recruitment, it’s going to report at some point in the next year or so. But the other thing that was very interesting to me was all the data about the node positivity because one of the debates we have in the clinic is around there’s one or two positive nodes, there are six being taken out by the surgeon because they thought it was low risk disease but now it’s node positive, should we irradiate the pelvic nodes, adds to the toxicity. I think that is another unresolved question.
AM: This is also something that affects us urologists since Alberto Briganti was covering this in his talk today. It was very, very nice.
NJ: Yes, it was a nice talk, yes.
AM: And he concluded that when you do it you should do it extended, even when you do it with a robot, open or laparascopic. I think will go along with that, to take out as many lymph nodes as possible to get staging results and, if possible, cure.
NJ: And from the radiation oncology, because we have this debate every week in our MDT, the more nodes that you guys take out the more morbidity there is from adding radiotherapy. So if you just do a sampling we can safely give radiotherapy, you don’t end up with legs like elephants’ legs. If you take out loads and loads and then we irradiate because they’re all positive then we’re in big trouble with the radiotherapy. So we flick-flack back and forth so our surgeons are currently doing a sampling level of procedure because then we know we can safely add radiotherapy after.
AM: Just up to fossa and not extendedly, what’s your…?
NJ: I have to say my anatomical knowledge of what the surgeons do is slightly hazy.
AM: Because I thought it would help you if you get the regions and know that there are positive lymph nodes in the external iliac vessels, would it help you from radiation wise where you have to…?
NJ: So the field that we would normally do, we would include the external iliacs down to the inguinal ligament and our standard pelvic field goes up to the aortic bifurcation. So with IMRT you can get the dose in.
AM: That’s interesting.
NJ: So I think the way that we will resolve this, though, is around things like PET imaging, we’re very excited about the PSMA PET data, we’ve been doing more and more of it.
EE: But I think now you’re becoming all too enthusiastic so I’ll bring you back to today. What about hypofractionation, since we’re still in radiation?
NJ: So there’s a lot of slightly arcane old data around the impact of fraction size on treating prostate cancer and the models predict that a bigger fraction size and fewer fractions should have a better therapeutic effect than the current way we do it which is a large number of small fractions. So there were two trials presented today, an RTOG one and a UK one, looking at different hypofractionations. The interesting thing about the hypofractionation trials was that they were non-inferiority trials so they showed essentially equal toxicity with a bigger dose per fraction which should increase the toxicity on normal tissues so you give a slightly lower dose to compensate for that. So it looked as if the models predicted correctly that you could hypofractionate, reduce the total dose a bit, get the same effect on the cancer but with a shorter treatment. Certainly in the UK, obviously the CHHiP trial was a UK trial, pretty much across the board people have switched practice. So we got off the plane from Vienna, which is when David Dearnaley first presented the data, and as a department we changed our practice that week across the board.
EE: So we’re going to tell our patients that you’re only going to take 20 days to finish?
NJ: Yes, 20 fractions instead of 37 was the change that we made so that’s a big change, big resource implications.
EE: For the future, for all these patients who are waiting in some public services to get in line to get radiation, for the cost for some people who come from a long distance, it makes a big difference.
NJ: It does and the thing that was striking about both of those trials is that they very impeccably collected toxicity data, both acute and late so that the data was very credible.
EE: But today you also presented some data on an arm that I thought was dropped and you surprised us.
NJ: Yes, we surprised ourselves, I have to say.
EE: OK.
NJ: So we set up the STAMPEDE trial to look at a number of agents and we’d picked some agents which were either in the clinical or heading there, zoledronic acid and docetaxel. Then we picked celecoxib because there was a lot of data both in vitro and epidemiological suggesting it had anti-prostate cancer effects. So we were looking to repurpose an existing drug if you like. We’re still trying to figure out what the data mean but essentially there appears to be a different effect of celecoxib in M0 and M1, so the effect was all in the M1, and then the second thing was that although we presented the zoledronic acid data as being negative there is evidence of a weak effect. So what we think is you add a weak effect from two different drugs and you end up with a less weak effect. So we came up with a survival advantage for celecoxib combined with zoledronic acid.
EE: Trying to defend it but it was a positive result.
NJ: It was a pre-planned analysis, the sub-analysis…
EE: Let me get an independent reviewer here. Karim, what do you think of that data?
KF: Very difficult to analyse it. As Nick just said, that was surprising, PFS was not met, overall survival seems to be met but it’s met only in combination with zoledronic acid and only for the M1 subgroup of patients. So we cannot exclude that this is just by chance, of course, because when you do subgroup analyses and everything and when you have multiple arms you can have just one positive by chance but it can also something true. It’s obviously impossible to know where we currently stand. I’m not sure that is going to change all the practice for tomorrow. Those two drugs are not approved in that setting and, again, because we cannot make sure it’s not just by chance, it’s probably not going to change how we treat these patients. But perhaps marginally it reminds us that we should also think again about integrating in clinical trials drugs that are not necessarily only anti-cancer drugs. I’m thinking, for example, about statins, about metformin, about aspirin; there are plans in Canada to do a randomised trial, a very large randomised trial in localised disease, testing some of these drugs. We also have plans to do that in Europe, perhaps within STAMPEDE, perhaps within the PEACE Consortium etc. We might find some good news with these old drugs, quite cheap, quite non-toxic, we’ll need to know that.
NJ: I was going to say, we’re adding, as you know, metformin into the STAMPEDE trial as a new arm, that will go live at some point this year.
EE: But whilst you were presenting all I could remember was all these patients who come into clinic with celecoxib on them and have stopped it because of the black box warning. 
NJ: Our DMC have obviously been monitoring that very carefully because this was obviously a concern. This was already known when we started the trial so we excluded patients with a cardiovascular history and we didn’t see any excess of cardiovascular problems in patients that we put in the trial. Now obviously that doesn’t mean it’s safe for all patients but it’s certainly safe for the patients we put in the trial and this is pretty mature follow-up now on 1,200 patients so it’s pretty robust data.
EE: So today, Karim, you presented data on a different type of design of a trial. Would you like to share some of the information?
KF: Sure. That’s really for patients receiving docetaxel for CRPC, classical docetaxel therapy for prostate prostate cancer who are benefitting from docetaxel. That’s typically the patients who have received, say, 6-10 cycles. When you decide to stop docetaxel and your patient is asking you, ‘Well, what’s next?’ and typically I’m telling the patients, ‘Well you go on vacation and I’ll see you again in two or three months from now,’ and after that when they’re coming back to me they’re progressing. So we probably need drugs to postpone progression when we’re stopping chemotherapy as we all do, probably, in breast cancer and other cancers, lung cancers etc. So it’s a switch maintenance concept that I wanted to test for prostate cancer. We did that with tasquinimod, which is an experimental drug and which was an experimental drug when we designed the trial, and that was a randomised trial for, again, these patients benefitting on docetaxel and stopping docetaxel, comparing tasquinimod versus placebo. The primary endpoint was radiographic progression free survival and it’s a positive trial. We were looking at a hazard ratio of 0.6 and this is exactly what we saw. Now, having said that, the drug is probably not going to be further developed because another pivotal phase III trial also reported positive PFS but negative overall survival so there is probably not going to be a big future for this compound. But I think the concept is interesting and we shall think about maybe new drugs to be tested post-docetaxel either in CRPC or in hormone sensitive disease. And this is probably the future for these patients.
EE: Immediately as you’re talking I think a lot of us are thinking, ‘Oh wow, his celecoxib could go into your design as well.’ All of these patients are on bone modifying agents anyway when they’re CRPC. So very exciting. What did you think about the circulating tumour cell story that Howard Scher presented today?
KF: Presented today, right. So basically what we know about CTCs is that, number one, that’s a quite strong prognostic factor but it’s not truly helpful for CRPC. You know that if a patient has a high CTC level he’s going to do bad as compared to patients with a low one but it is as it is.
EE: Do you use it in your clinic?
KF: No because it’s expensive and for basically no true information. Now, more interesting is that in the context of clinical trials it’s a nice way probably to measure response to a given drug, at least to some drugs. But still it’s an expensive way to measure response compared to PSA response, clinical assessment and radiographic assessment. But it is something. Perhaps more interesting is when you’re trying to look at molecular analysis on CTCs, and this is really an open field and this is something that we’re trying to do, say if we can look at ARV-7 etc. to better decide which drug should be used. Today Howard looked at basically the shape of the cells with different patterns and he could show that there is obviously heterogeneity, which is something we were suspecting already, and that, depending on the subgroup of patients, based on the CTC shape if you will, your patient might or might not benefit from abiraterone, enzalutamide, while taxane seems to be active in the various subgroups. So we’re learning more and more. It’s not going to change our practice tomorrow, for sure, but we’re making progress with regards to CTC I believe.
EE: His data reminded me very much of Bova’s paper in the way that Bova this year, and I’m going to talk about that tomorrow, went and looked at all the heterogeneity of the clones and metastases, the sub-clones and metastases. It would be nice to see that next generation of actually looking at those tumour samples and the heterogeneity in those circulating tumour cells.
KF: I agree.
EE: So overall what would you say was today’s take home message for us in the field of prostate cancer?
KF: I guess it has to come back to overall survival and we heard today a trial that showed overall survival, this is the one that Axel summarised. It’s a bicalutamide trial on top of radiation for patients with a rising PSA post-local treatment and overall survival was met in this trial so I guess this is very important. On top of that we need to remember that we need to be patient with prostate cancer. That trial was actually designed in the mid-90s, which is twenty years ago, and it took twenty years before we had overall survival data to change our practice for tomorrow as we all said. This is very important and again this is an academic trial that was not an industry sponsored trial because we needed the time. So that is also important to remember.
EE: Thank you very much for your comments, gentlemen. Thank you very much for attending this session.